We seek to understand the molecular mechanism underlying the tissue degeneration characteristic of human amyloid diseases and to use this insight to develop new therapeutic strategies and diagnostics to ameliorate the human amyloidoses. In specific aim 1, we focus on understanding why aging is such an important risk factor for the onset of the transthyretin amyloidoses. All indications are that amyloid diseases do not result from slow, progressive accumulation of amyloid fibrils over a lifespan. Instead, an aging-related physiological change appears to trigger their onset. Since transthyretin is synthesized and degraded by the liver, and since liver transplantation from an amyloid patient into a liver cancer patient initiates rapid amyloidosis in the latter, we are confident that studying liver physiology in amyloidosis, and normal young and old donors will reveal important clues about the etiology of this disease. In specific aim 2, we utilize first-in-class amyloidogenesis inhibitors to test the amyloid hypothesis in two placebo-controlled human clinical trials. We will also fractionate specific aggregate morphologies, arrest these intermediates from further assembly and assess their toxicity. Additionally, new technology will be developed to characterize amyloid deposits in the context of the oxidative-metabolite pool, which could contribute to these maladies. In specific aim 3, we will continue to develop new therapeutic strategies centered around the discovery of secretion modulators, compounds that make cells less permissive to the secretion of highly destabilized amyloidogenic proteins. Unlike the transthyretin-disease specific native state kinetic stabilizers discovered in the last funding period, these compounds should be useful in treating numerous amyloid diseases. Lastly, we seek to develop positron emission tomography (PET) diagnostics to image the earliest aggregates appearing in amyloid diseases in living subjects to enable treatment to begin before substantial tissue degeneration occurs. [unreadable] [unreadable] [unreadable]